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Detailed Alzheimer's Disease Timeline Revealed

First Results From the DIAN Study Published Caroline Cassels Authors and Disclosures
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July 11, 2012 The first published results from a study of individuals genetically destined to develop a rare and aggressive form of Alzheimer's disease (AD) suggest that preclinical changes may occur long before the onset of symptoms such as cognitive decline and memory loss.

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Results from the prospective, longitudinal study, which was conducted in persons who are mutation carriers (MCs) for autosomal-dominant AD, indicate that measurable biochemical and imaging markers, including changes in cerebrospinal fluid (CSF), brain amyloid deposition, and brain metabolism, can be detected up to 25 years before symptoms appear. "A series of changes begins in the brain decades before the symptoms of Alzheimer's disease are noticed by patients or families, and this cascade of events my provide a timeline for symptomatic onset," first author Randall Bateman, MD, Washington University School of Medicine in St. Louis, Missouri, said in a statement. "As we learn more about the origins of Alzheimer's to plan preventive treatments, this Alzheimer's timeline will be invaluable for successful drug trial," Dr. Bateman added. According to Laurie Ryan, PhD, clinical trials program director at the National Institute on Aging, which is one of the organizations that provided funding for the study, the findings may ultimately have important implications for the most common form of the disease. "While DIAN [Dominantly Inherited Alzheimer's Network] participants are at risk for the rare, genetic form of the disease, insights gained from the study will greatly inform our understanding of late-onset Alzheimer's disease," Dr. Ryan said in a statement.

Dr. Randall Bateman

MOST POPULAR ARTICLES ! Published online July 11 in the New England Journal of Medicine, these findings from the ACCORDING TO PSYCHIATRISTS

DIAN study were first presented last year at the Alzheimer's Association International Conference and were reported by Medscape Medical News at that time. Measurable Changes One of the major challenges of understanding the magnitude and pathologic processes of late-onset AD, the researchers note, is that the disease develops over many years. From a research standpoint, autosomal-dominant AD offers the advantage of a predictable age of onset and "an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease." Autosomal-dominant mutation carriers (MCs) are destined to develop AD when they are in their 40s, 30s, and sometimes 20s. The DIAN study included 128 MCs who were cognitively normal. All participants underwent baseline clinical and cognitive assessments, brain imaging, as well as CSF and blood testing. The investigators used the participants' age at baseline assessment and their parents' age of symptom onset of AD to calculate the estimated years to symptom onset. The investigators found that MCs had lower levels of !-amyloid 42 (A!-42) and elevated levels of tau and phosphorylated tau (p-tau) compared with their nonmutation carrier siblings. "Family members without the Alzheimer's mutations have no detected change in the markers we tested. It's striking how normal the Alzheimer's markers are in family members without a mutation," said Dr. Bateman. Specifically, the authors report that concentrations of A!-42 in the CSF of MCs appeared to decline 25 years before expected symptom onset. In addition, A! deposition in the brain, as measured by positron emission tomography (PET) using the Pittsburgh compound B, was detected 15 years before expected symptom onset. Further results revealed an increase in concentrations of tau protein in the CSF and an increase in brain atrophy, which were detected 15 years before expected symptom onset. In addition, the investigators report that memory loss and cerebral hypometabolism occurred 10 years before expected symptom onset. Global cognitive impairment as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale was detected 5 years before expected symptom onset. Finally, the authors report that patients met diagnostic criteria for dementia an average of 3 years after expected symptom onset. Promise of Prevention Commenting on the study for Medscape Medical News, William Thies, PhD, chief medical and scientific officer of the Alzheimer's Association, said the study marks "the realization of the promise of DIAN. It is not the end of process but would seem to indicate the investment is worthwhile." Dr. Thies added that there has been a model of AD biomarkers for several years. However, he noted these latest data suggest that the model is correct. These are "strong confirmatory data that support previous ideas," he said. Although there are no immediate clinical implications, he added that "in the future, these results suggest that we may be able to treat AD 15 years before dementia occurs and hence prevent the dementia." He added that this is a rapidly developing area and one physicians should keep an eye on. According to Dr. Thies, a key remaining question is whether these findings are generalizable to the late-onset AD population. Dr. William Thies

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"This is yet to be determined. There are many reasons to think that dominantly inherited AD is the same as lateonset AD, but this will have to be proven in studies like DIAN. These data certainly suggest they are the same," he said. Dr. Bateman is leading the development of AD prevention and treatment trials in DIAN participants, which investigators hope to launch later this year. DIAN researchers offer an expanded registry for families with inherited Alzheimer's mutations. Anyone with a family history of multiple generations of AD diagnosed before age 55 years can visit www.DIANXR.org to register for follow-up contact from researchers to determine whether their family is eligible for participation in DIAN studies. The study was funded by the National Institute on Aging. N Engl J Med. Published online July 11, 2012.

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